Neopterin
is released from human monocyte-derived macrophages upon stimulation
with interferon-gamma and is a sensitive indicator for cellular
immune activation. Furthermore, reactive oxygen species (ROS) are
produced in case of immune activation and inflammation. In a
cross-sectional approach, plasma concentrations of neopterin and of
antioxidant compounds and vitamins were compared in 1463 patients
investigated by coronary angiography, which were recruited within the
LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. Serum
neopterin concentrations were higher in patients with coronary artery
disease (CAD; mean+/-S.D.: 8.7+/-7.3 nmol/L) compared to controls
(7.4+/-5.0 nmol/L; Welch's t-test: p<0.001). Mean concentrations
of ascorbic acid (p<0.0001), gamma-tocopherol (p<0.05),
lycopene (p<0.001), lutein+zeaxanthin (p<0.05), alpha-carotene
(p<0.05) and beta-carotene (p<0.05) were lower in CAD than in
controls. Neopterin concentrations correlated with CAD-score
(r(s)=0.156; p<0.0001) and inversely with antioxidants lycopene
(r(s)=-0.277; p<0.0001) and lutein+zeaxanthin (r(s)=-0.175;
p<0.0001) levels and with vitamins ascorbic acid (r(s)=-0.207;
p<0.0001) and alpha-tocopherol (r(s)=-0.105; p<0.0001). The
study demonstrates that higher neopterin production is associated
with lower concentrations of antioxidant compounds in patients at
risk for atherosclerosis. Results suggest that lower concentrations
of antioxidant compounds may relate to higher grade of chronic immune
activation in patients.

In vitro, large amounts of neopterin are produced by human
monocytes/macrophages upon stimulation with interferon-gamma. In vivo
increased neopterin concentrations in human serum and urine indicate
activation of cell-mediated (Th1-type) immune response, e.g., during virus
infections, autoimmune diseases, allograft rejection and in certain types
of malignancy. In various groups of patients with malignant diseases
neopterin concentrations correlate to the stage of disease, and higher
neopterin concentrations in serum, urine or ascitic fluid were shown to
significantly predict worse prognosis regarding relapse and survival. The
amounts of neopterin produced by activated monocytes/macrophages correlate
with their capacity to release reactive oxygen species (ROS). With this
background, neopterin concentrations in body fluids can be regarded as an
indirect estimate of the degree of oxidative stress emerging during
cell-mediated immune response. Moreover, recently neopterin was found
itself to be capable of enhancing toxic effects induced by ROS. In vitro,
neopterin derivatives were able to interfere with intracellular signal
transduction pathways involved in, e.g., programmed cell death and the
induction of proto-oncogene c-fos or nuclear factor-chi B. The data support
the view that increased production of ROS--indicated by increased neopterin
concentrations--could modulate the development, the proliferation and the
survival of malignant cells.

We previously
demonstrated the presence of advanced oxidation protein products (AOPP), a
novel marker of oxidative stress in the plasma of uremic patients receiving
maintenance dialysis. The present study in a cohort of 162 uremic patients
showed that plasma concentrations of AOPP increased with progression of
chronic renal failure and were closely related to advanced glycation end
products (AGE)-pentosidine (r = 0.52, p < 0.001), taken as a marker of
AGE. In vivo, the relevance of AOPP and AGE-pentosidine in
monocyte-mediated inflammatory syndrome associated with uremia was
evidenced by close correlations between AOPP or AGE-pentosidine and
monocyte activation markers, including neopterin, IL-1R antagonist,
TNF-alpha, and TNF soluble receptors (TNF-sR55 and TNF-sR75). To determine
the mechanisms by which AOPP and AGE could be directly involved in monocyte
activation, AOPP-human serum albumin (HSA) and AGE-HSA were produced in
vitro by treating HSA with oxidants or glucose, respectively. Spectroscopic
analysis confirmed that AOPP-HSA contains carbonyls and dityrosine. Both
AOPP-HSA and AGE-HSA, but not purified dityrosine, were capable of
triggering the oxidative burst of human monocytes in cultures. The
AOPP-HSA-induced respiratory burst was dependent on the chlorinated nature
of the oxidant and on the molar ratio HSA/HOCI. Collectively, these data
first demonstrate that AOPP act as a mediator of oxidative stress and
monocyte respiratory burst, which points to monocytes as both target and
actor in the immune dysregulation associated with chronic uremia.

Oxygen
is required by eukaryotic cells for energy production. Living in an aerobic
environment brings with the exposure of cells to reactive oxygen species
(ROS). ROS for example accumulate as byproducts of the aerobic metabolism,
and a substantial endogenous generation of ROS occurs during immune
response by immunocompetent cells. Massive occurrence of ROS results in
oxidative damage of cellular components. The primary targets of ROS are
enzymes, cell membranes, and DNA. Oxidative stress is defined by an
overwhelming occurrence of ROS opposed by an exhausted pool of
antioxidants. In the last decade, the role of oxidative stress in the
pathogenesis of a wide range of human diseases became obvious, and
determination of the phenomenon of oxidative stress moved into the focus of
interest. Several approaches were developed to quantify this condition.
Among them are measurements of oxidation products such as lipid
peroxidation, oxidized protein, or DNA. Alternatively, oxidative stress can
be determined by the loss of antioxidants. This review briefly summarizes
current available methods for the quantification of oxidative stress in
vivo.